Nitrile oxides in medicinal chemistry. 3. Synthesis and bioenantioselectivity of (+)- and (-)-2-methyl-5-[(dimethylamino)-methyl]-3-oxo-isoxazolidine methiodide.
The two enantiomers of the potent muscarinic ligand 2-methyl-5[(dimethylamino)methyl]-3-oxo-isoxazolidine methiodide [(+/-)-V] were synthesized in a very high enantiomeric excess (98.8 and greater than 99%). The muscarinic activity of the two enantiomers was assayed on the isolated guinea pig ileum and atria, and on rat jejunum and urinary bladder and the nicotinic activity was evaluated on the frog rectus abdominis muscle. (R)-(-)-V, the most potent enantiomer in the muscarinic tests, has the same absolute configuration as [2R,5R]-muscarone and, like muscarone, has a low eudismic ratio (ER: 2.5-10.4). In the nicotinic assay, (S)-(+)-V was found to be the eutomer (ER: 3.5).
De Amici
M
M
Istituto Chimico-Farmaceutico, Università di Milano, Italy.
De Micheli
C
C
Grana
E
E
Lucchelli
A
A
Zonta
F
F
D000818:Animals; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007583:Jejunum / Q000187:drug effects; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D010277:Parasympathomimetics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011893:Rana esculenta; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000187:drug effects; D013237:Stereoisomerism; D001743:Urinary Bladder / Q000187:drug effects
D007555:Isoxazoles; D010277:Parasympathomimetics; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; C067275:2-methyl-5-((dimethylamino)methyl)-3-oxoisoxazolidine methiodide